1. Field of the Invention
The present invention relates to a novel barium powder preparation and application thereof to an extremely high density barium suspension used mainly for upper gastrointestinal double contrast examination, processes for producing them, and a method of X-ray examination applicable mainly to the diagnosis of early gastric cancer and peptic ulcer using said extremely high density barium suspension as a contrast medium.
2. Background Art
The X-ray examination of the stomach, duodenum and esophagus, especially for the double contrast method, requires highly skilled operation using gastric tubes, due to the fuzziness of the barium sulfate suspension (referred to simply as "barium" hereafter) used as a contrast medium, or its excessive or insufficient adhesion to the gastric mucosa, as is often the case. Improvement has long been awaited, as no ideal barium is commercially available yet. Although new products claiming "high density" have been released for the last few years, their densities in practical use are only about 200 W/V%, and fall short of addressing the aforementioned problems.
The environment surrounded by gastric mucosa is unique and severe, containing free acids and some mucus in an ordinary way. The mucosal surface is covered with the protecting layers of mucus, such as Mackintosh's barrier mucus and Katsuyama's surface mucous gel layer (SMGL), and not easily accessible. Even a time-tested barium with a density of 140 W/V% (Baritogen DX, tradename of Fushimi Seiyakusho Co. Ltd.) would require, for a double contrast examination, a number of rigorous body rolling operations to wash out the mucous layers, in addition to the use of a gastric tube to remove the free gastric mucus, to obtain a preferable result.
Body rolling is an operation to change the patient's posture by turning the patient's body on a horizontal table by 90.degree. alternately to the bilateral sides from the supine position. If the amount of mucus is large, it needs to be sucked out through a gastric tube. However, it is practically not easy to suck out dense gastric mucus. For example, the insertion and removal of a gastric tube may be difficult in some patients. Also, inserting a gastric tube may induce unexpected secretion of gastric juice or peristalsis, bringing about an adverse effect. Furthermore, the double contrast examination requires time-consuming air injection through a gastric tube while monitoring the amount of injection using a large cylinder. Therefore, a significant amount of parasympathicolytic usually needs to be administered in advance to suppress the peristalsis and mucous secretion during the injection intramuscularly and, at times, both intramuscularly and intravenously. These complicated procedures make most non-specialists hesitant to use this examination method.
There is a huge amount of literature, including books and journals, on the detailed procedures available in Japan. For example, the rolling method for double contrast radiography has been frequently described with diagrams called "Stomap" and detailed explanation, such as the position, direction and angle of posture change.
Weirdly, however, no clear description has been provided on the speed of rolling. Instructions previously given require to roll as quickly as possible, rock or wash, or swing the hips as an Hawaiian dance. These seemingly descriptive but quite vague expressions may not help a lot in practice.
As mentioned above, the double contrast radiography of the stomach depends largely on the skills of the operator, due to the complexity of the conditions such as the complicated environment of the gastric mucosa, difference in barium density, visco-elasticity of individual contrast medium, and rolling method. From the viewpoint of rolling mechanics in double contrast examination, a barium density of 140 W/V% or less requires quick and repeated rolling until the barium forms a desired thin layer over the gastric mucosa in order to remove the mucus. However, excessive rolling may result in insufficient adhesion of the barium to the gastric mucosa, as the barium density may decrease due to dilution by the mucus.
The lately commercialized high-density agents with rated barium densities of 200 W/V% or over have a common disadvantage of easily precipitating and forming sludge. This overly high visco-elasticity hampers spreading of the medium and makes it a too thick layer and, therefore, visualizes only the gastric folds but not the gastricae area. A super-high density agent (tradename: EZ-HD) produced by an U.S. company with a barium density of 250 W/V% has the disadvantage of forming an excessively thick barium layer that cannot be reduced no matter how quick or repetitively rolling is done.
A high-density preparation of barium sulfate used as an X-ray double contrast medium is available from China (manufactured by National Chintao Tonfon Chemical Factory). The supplied technical document says it may be used for the X-ray double contrast examination of the esophagus and stomach. In use, 500 g of powder are mixed with an appropriate amount water and stirred for 5 minutes to make a suspension. It needs to be stirred again immediately before use for uniformity. Combination with an effervescent agent (Chintao No. 3) is recommended for a better result. In the supplied barium density dilution table, 39 ml of water is used to prepare a 300 g of 280 W/V% suspension with a total amount of 107 ml and a viscosity of about 300 mPa.multidot.s. Assuming 1 cp as 1 mPas.multidot.s, the viscosity is twice that of the applicant's extremely high density barium, which is 150 cp (see Table 7) at an equal density of 280 W/V%.
An analysis by the applicant revealed that the agent contains almost no small particles and is composed chiefly of large particles which have a specific surface area of 0.206 m.sup.2 /g and a particle size distribution with a steep peak at 10 .mu.m. Its scanning electron microscope image shows that it is made of crushed particles of natural barite. Unknown additives account for a mere 0.05%. The biggest problem is that, because it is made of crushed particles, the appearance is not clear white, unlike commonly available agents, posing a risk of contamination by foreign matter other than pure barium. A second problem is that it easily precipitates, as is the case for agents composed of large particles and no small particles. The large particles are similar to the large component particles of the present invention, but slightly larger. The rated density excludes the additives. As mentioned above, this barium sulfate has an apparent viscosity twice as high and no distinctive properties.
Also, another technology related to high-density barium has been proposed (Laid-open Japanese Patent Application No.60-54919, "A Process for Producing Barium Sulfate with Increased Fluidity and Density Suitable as a Contrast Ingredient in X-Ray Contrast Medium, Products Obtained by the Process, and an X-Ray Contrast Medium Produced Therefrom").
The technology can be summarized as follows: First, the pure barium (synthetic) used as a material is impregnated with ammonium sulfate and other salts, and sintered at a high temperature of 800 to 1200.degree. C. This step removes the edges of the crystals to make their surface round and flat, allowing significantly efficient packing. The preferred particle size of the material is 1 to 5 .mu.m. After the above step, a suspension of this powder, to which an appropriate amount (3%) of a few composite assistants have been added, has a density of 200 W/V% and a viscosity no more than 1000 mPas.multidot.s. Assuming 1 cp as 1 mPas.multidot.s, this barium sulfate has an extraordinarily high viscosity. The detailed description of the invention refers to barium sulfate agents obtained from crushed natural barite, or so-called crushed particles, and points out, by citing the argument by E. Miller, that "regrettably they generally do not meet the standard purity of the medical literature (Pharmacopoeia) as they contain excessive amounts of heavy metals."
Also, another technology related to high-density barium has been proposed (Laid-open Japanese Patent Application No.60-61537, "An X-Ray Contrast Medium").
This X-ray contrast medium is a powder agent having two peaks in the particle size distribution, one of which is in the large and the other of which in the small region, containing lignin sulfonic acid and alkali citrate as surfactants to decrease the viscosity and increase the stability of the barium suspension. Both of these two additives have been known to decrease viscosity (former in West German Patent No. 2028025, and latter in U.S. Pat. No. 3,216,900). However, the technology seeks a synergistic effect of using them together. For the particle size distribution with two peaks, Vol. 35, p.95, Journal of the Osaka Medical School, 1976, by the applicant is cited.
As a result, a viscosity of 60 sec (DAB8) was obtained at 2.5 g/ml (250 W/V%). Compared to the viscosity of 80 to 110 sec of the aforementioned Chinese barium sulfate at 250 W/V%, it is significantly low. However, no reference is made to the viscosity at an extremely high density of 260 W/V% or above, or to specific clinical performance.